DOI: 10.1084/jem.20112457. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice [Penn]

Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice

10.1084/jem.20112457

Crossref journal-article

Rockefeller University Press

Journal of Experimental Medicine (291)

Abstract

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson’s disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell–cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.

Bibliography

Luk, K. C., Kehm, V. M., Zhang, B., OâBrien, P., Trojanowski, J. Q., & Lee, V. M. Y. (2012). Intracerebral inoculation of pathological Î±-synuclein initiates a rapidly progressive neurodegenerative Î±-synucleinopathy in mice. Journal of Experimental Medicine, 209(5), 975â986.

Authors 6

Kelvin C. Luk (first)
Victoria M. Kehm (additional)
Bin Zhang (additional)
Patrick O’Brien (additional)
John Q. Trojanowski (additional)
Virginia M.Y. Lee (additional)

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Dates

Type	When
Created	13 years, 4 months ago (April 17, 2012, 1:29 a.m.)
Deposited	2 years, 1 month ago (July 25, 2023, 9:02 p.m.)
Indexed	1 hour, 36 minutes ago (Aug. 27, 2025, 12:02 p.m.)
Issued	13 years, 4 months ago (April 16, 2012)
Published	13 years, 4 months ago (April 16, 2012)
Published Online	13 years, 4 months ago (April 16, 2012)
Published Print	13 years, 3 months ago (May 7, 2012)

Funders 0

None

BibTeX

@article{Luk_2012, title={Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice}, volume={209}, ISSN={0022-1007}, url={http://dx.doi.org/10.1084/jem.20112457}, DOI={10.1084/jem.20112457}, number={5}, journal={Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Luk, Kelvin C. and Kehm, Victoria M. and Zhang, Bin and O’Brien, Patrick and Trojanowski, John Q. and Lee, Virginia M.Y.}, year={2012}, month=apr, pages={975–986} }

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